The present invention relates to the naphthyridone antibiotic alatrofloxacin mesylate essentially free of less polar impurities, to parenteral compositions of said alatrofloxacin mesylate and to processes for purifying alatrofloxacin mesylate.
Alatrofloxacin mesylate is the mesylate prodrug salt of related naphthyridone antibiotic trovafloxacin. Alatrofloxacin mesylate, prepared by methods currently available is produced in very high purity. However, alatrofloxain mesylate prepared by these current methods contains minute less polar impurities that tend to precipitate from parenteral compositions after standing for indefinite periods. These less polar impurities can not be adequately removed by commercially feasible methods such as recrystallization, standard chromatographic means using flash silica gel, solventisolvent extraction methods, or by treatment with diatomaceous earth. The present inventors have discovered that the impurities can be successfully removed by treating the crude reaction products, i.e. product prepared by any of the currently known literature methods, with a polystyrene resin.
It has been previously known that the quinolone antibiotic ciprofloxacin also possesses impurities rendering the product unsuitable for parenteral formulation. European Patent Publication 287,926, published Oct. 26, 1988, describes the purification of ciprofloxacin by treatment with diatomaceous earth so as to yield a product that is suitable for parenteral formulation. As stated above, treatment of alatrofloxacin mesyiate with diatomaceous earth does not adequately remove the less polar impurities.
The antibacterial activity and synthesis of the aforementioned alatrofloxacin are described in U.S. Pat. Nos. 5,164,402 and 5,229,396 issued Nov. 17, 1992 and Jul. 20, 1993, respectively, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application.
lnternational Patent Publication WO 97/00268, published Jan. 3, 1997, claims an alternative process for preparing alatrofloxacin. The foregoing publication is hereby incorporated by reference in its entirely.
International Patent Publication WO 97/08191, published Mar. 6, 1997, describes a third process for the preparation, and polymorphs thereof, of alatrofloxacin, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent publication is assigned in common with the present application.
International Patent Publication WO 95/19361, published Jul. 20 1995; U.S. patent application No. 60/021,419, filed Jul. 9, 1996; and International Patent Application No. PCT/EP96/04782, filed Oct. 31, 1996, claim novel intermediates for preparing alatrofloxacin and trovafloxacin, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patent publications and applications are assigned in common with the present application.
U.S. Pat. No. 5,475,116, issued Dec. 12, 1995, and U.S. Pat. No. 5,256,791, issued Oct. 26, 1993, claim various azabicyclohexane intermediates useful in the synthesis of alatrofloxacin and trovafloxacin, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application.
U.S. patent application Ser. No. 08/764,655, filed Dec. 2, 1996, refers to methods of treating Helicobacter pylori infections with alatrofloxacin and trovafloxacin, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent application is assigned in common with the present application.
International Patent Publication WO 96/39406, published Dec. 12, 1996 claims a novel crystal form of anhydrous 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino3-azabicyclo[3.1. 0]hex-3-yl)6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro4-oxo-1,8-naphthyrid ine-3-carboxylic acid, methanesulfonic acid salt, a method of using said compound in the treatment of a bacterial infection in mammals, especially humans, and to pharmaceutical compositions, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent publication is assigned in common with the present application.
International Patent Application PCT/IB 96/00756, filed Jul. 29, 1996, claims zwitterionic forms of trovafloxacin which are useful for the administration of the drug as a suspension, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent application is assigned in common with the present application.